title: Incomplete surgical resection of ductal carcinomas in situ results in activation of ERBB2 in residual breast cancer cells.
abstract: ERBB2 amplification and consecutive overexpression is a predictor for poor prognosis in breast cancer patients. In addition, incomplete resection of ERBB2-overexpressing tumors leads to increased proliferation of residual breast cancer cells. While the local release of cytokines is thought to be responsible for the malignant behavior of remaining tumor tissue, the exact mechanism is still unknown. We have analyzed epidermal growth factor receptor (EGFR), activated (p)EGFR, and activated (p)ERBB2 protein expression in ERBB2-overexpressing and in non-ERBB2-overexpressing tumors from patients who underwent breast surgery and consecutive re-excision for involved margins, and compared expression levels by immunohistochemistry. While overall ERBB2 protein expression in the initial and the re-excised sample were comparable, we observed an increase in pERBB2 in ductal carcinomas in situ in both, ERBB2-overexpressing (16/21 vs 24/24; P=0.018, chi(2) test) and non-ERBB2-overexpressing tumors (3/28 vs 5/12; P=0.025, chi(2) test). pERBB2 was not increased in invasive tumors, regardless on whether the samples had been taken from a ERBB2-overexpressing (9/25 vs 6/17; P=0.261, chi(2) test) or a non-ERBB2-overexpressing tumor (1/27 vs 0/8; P=0.581, chi(2) test). EGFR expression was only detected in 1/47 ERBB2-overexpressing primary tumors and 2/48 non-ERBB2-overexpressing tumors, and was undetectable in re-excised specimen. Taken together, we have demonstrated an increase in ERBB2 receptor activation in incompletely resected preinvasive breast cancer. We hypothesize that receptor phosphorylation is caused by growth factor stimulation in response to intraoperative tissue damage, and perioperative inhibition of specific cytokines could become a promising therapeutic strategy.
authors.affiliation: Department of Obstetrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. christian.singer@meduniwien.ac.at
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Gernot
authors.initials: G
authors.lastname: Hudelist
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Fuchs
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Köstler
authors.forename: Anneliese
authors.initials: A
authors.lastname: Fink-Retter
authors.forename: Daphne
authors.initials: D
authors.lastname: Gschwantler-Kaulich
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lamm
authors.forename: Margarethe
authors.initials: M
authors.lastname: Rudas
authors.forename: Klaus
authors.initials: K
authors.lastname: Czerwenka
authors.forename: Ernst
authors.initials: E
authors.lastname: Kubista
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002278:Carcinoma in Situ / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D044584:Carcinoma, Ductal / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000378:metabolism* / Q000473:pathology; D020890:Neuregulin-1 / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human